This proposal is for advanced training and mentored research for Dr. Nahvi to become an independent investigator in tobacco control among vulnerable populations. Building on intensive mentorship, didactic programs, and a strong research environment, the proposed research and career development plan will allow Dr. Nahvi to expand her training in the design and conduct of clinical trials; smoking cessation research methods; and the development and evaluation of tailored behavioral interventions for drug users. This training will foster Dr. Nahvi's development as an independent clinical investigator and guide a future R01 grant application to conduct a randomized trial of a tailored smoking cessation intervention for methadone maintained smokers. This proposal addresses two challenges in tobacco control research: 1) Determining effective interventions among populations with a disproportionately high tobacco use prevalence; and 2) promoting adherence to smoking cessation interventions. There is a marked prevalence of tobacco use and tobacco-related disease among methadone maintenance patients. Varenicline's demonstrated efficacy may not be generalizable to methadone maintained smokers because of poor adherence, which is highly prevalent among drug users. Adherence to smoking cessation medication is strongly associated with cessation, and is one of the few factors shown to increase cessation among methadone maintained smokers, but strategies to promote smoking cessation medication adherence have not been evaluated in methadone patients. Based on the Information, Motivation, and Behavior model, we propose a directly observed therapy (DOT)-based intervention targeting behavioral skills necessary for optimal adherence. Because methadone clinic-based DOT interventions have been shown to improve medication adherence and clinical outcomes in HIV and TB, we propose to determine in a randomized trial whether DOT varenicline provided at a methadone clinic is more efficacious than self- administered varenicline for promoting smoking cessation and enhancing adherence. We will also evaluate moderating effects of drug and alcohol use and psychiatric symptoms on DOT effects. PUBLIC HEALTH RELEVANCE: Reducing tobacco use and increasing smoking cessation attempts among adults are objectives of Healthy People 2010, and determining strategies to increase use of proven cessation treatments was identified as a priority in the NIH State-of-the-Science statement on tobacco use. We hope to help methadone maintained smokers quit smoking by developing and evaluating an intervention to optimize smoking cessation medication use among methadone maintained smokers. If effective, this intervention has the potential to prevent cancer and other smoking-related diseases, and may save lives.